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. 1999 Nov;73(11):9576-83.
doi: 10.1128/JVI.73.11.9576-9583.1999.

Pathogenesis of experimental rhesus cytomegalovirus infection

K M Lockridge  1 , G Sequar, S S Zhou, Y Yue, C P Mandell, P A Barry
Affiliations

Pathogenesis of experimental rhesus cytomegalovirus infection

K M Lockridge et al. J Virol. 1999 Nov.

Abstract

Human cytomegalovirus (HCMV) establishes and maintains a lifelong persistence following infection in an immunocompetent host. The determinants of a stable virus-host relationship are poorly defined. A nonhuman primate model for HCMV was used to investigate virological and host parameters of infection in a healthy host. Juvenile rhesus macaques (Macaca mulatta) were inoculated with rhesus cytomegalovirus (RhCMV), either orally or intravenously (i.v. ), and longitudinally necropsied. None of the animals displayed clinical signs of disease, although hematologic abnormalities were observed intermittently in i.v. inoculated animals. RhCMV DNA was detected transiently in the plasma of all animals at 1 to 2 weeks postinfection (wpi) and in multiple tissues beginning at 2 to 4 wpi. Splenic tissue was the only organ positive for RhCMV DNA in all animals. The location of splenic cells expressing RhCMV immediate-early protein 1 (IE1) in i.v. inoculated animals changed following inoculation. At 4 to 5 wpi, most IE1-positive cells were perifollicular, and at 25 wpi, the majority were located within the red pulp. All animals developed anti-RhCMV immunoglobulin M (IgM) antibodies within 1 to 2 wpi and IgG antibodies within 2 to 4 wpi against a limited number of viral proteins. Host reactivity to RhCMV proteins increased in titer (total and neutralizing) and avidity with time. These results demonstrate that while antiviral immune responses were able to protect from disease, they were insufficient to eliminate reservoirs of persistent viral gene expression.

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Figures

FIG. 1
FIG. 1
Western blot analysis of plasma from inoculated animals. Longitudinal plasma samples from p.o. (30460) and i.v. (29840, 29740, and 29848) inoculated animals were evaluated by Western blotting for reactivity to RhCMV antigens. The time points for each plasma sample (wpi) are given below each lane. Molecular masses are shown at the right and left.
FIG. 2
FIG. 2
PCR analysis of RhCMV DNA in inoculated animals. Longitudinal plasma samples (top panels) and tissues obtained at necropsy (bottom panels) from p.o. (left panels) and i.v. (right panels; 29840, 29740, and 29848 only) inoculated (Inoc.) animals were analyzed for RhCMV DNA. For plasma samples, wpi are shown (week 0 was not available for animals 29831 and 29762). Samples with a positive signal (+) are indicated. Tissue samples analyzed were axillary LN (lanes 1), bone marrow (lanes 2), pancreas (lanes 3), ileum (lanes 4), inguinal LN (lanes 5), jejunum (lanes 6), kidney (lanes 7), lung 1 (lanes 8), lung 2 (lanes 9), submandibular gland (lanes 10), spleen (lanes 11), thymus (lanes 12), tonsil (lanes 13), liver (lanes 14), parotid gland (lanes 15), and esophagus (p.o. inoculated animals only) and duodenum (i.v. inoculated animals only) (lanes 16). Lane P, positive control tissue; lane M, molecular weight markers.
FIG. 3
FIG. 3
Immunohistochemical localization of RhCMV IE1-expressing cells in the spleen. (A to C) Spleen sections from animals 29840 (A), 29740 (B), and 29848 (C) were assayed for RhCMV IE1 expression. IE1-positive cells are brown (DAB), and the cells are counterstained with hematoxylin (blue). The location of a representative follicle (f) is indicated. (D and E) Cells were double labeled for IE1 expression and markers for endothelial cells (D) or macrophages (E). (D) Endothelial cells are brown, and IE1-positive cells are purple. (E) Macrophages are pink, and IE1-positive cells are brown. Double-labeled cells are indicated by arrows. Many of the IE1-expressing cells are not stained with either cell type marker.
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